The long-term goals of my research are to increase our understanding of the molecular mechanisms that promote the development and progression of pathological cardiac hypertrophy. In pursuit of this goal, my laboratory has new data suggesting the RNA binding protein Human antigen R (HuR) is a novel mediator of pathological cardiac hypertrophy. HuR is activated downstream of pro-hypertrophic signaling mediators such as phenylephrine and angiotensin, and although it is highly expressed in cardiac myocytes, very little is known concerning the functional role of HuR in the heart. New preliminary data from my lab shows that HuR is activated in hypertrophic myocytes, and cardiac-specific deletion of HuR prevents pathological hypertrophy in response to pressure overload. Thus, our central hypothesis is that activation of HuR in the cardiac myocytes promotes pathological cardiac hypertrophy, while ablation of HuR is protective. Aim 1 will determine the functional impact and downstream signaling of HuR in pathological cardiac hypertrophy. The working hypothesis for is that development of pathological hypertrophy and the cardiac remodeling associated with the transition from the compensated to de-compensated state will be reduced in cardiac-specific HuR deletion mice following transverse aortic constriction (TAC). We have developed an inducible cardiac-specific HuR deletion mouse that will allow us to examine the clinically relevant scenario of HuR deletion before and after the initial hypertrophic stimulus to determine whether blockade of HuR at a later time point can and delay or rescue pathological progression of hypertrophy to heart failure. Aim 2 will identify the upstream signaling pathways that lead to HuR activation in myocytes and determine the functional impact of HuR in Gq-mediated hypertrophy. The working hypothesis is that HuR is a novel downstream signaling mediator of Gq-coupled GPCR-induced pathological hypertrophy. Activation of Gq-protein is observed in nearly every form of pathological hypertrophy, but the specific mechanisms by which its activation results in cardiac pathology have yet to be fully elucidated. Thus, our results are poised to make a significant impact in how we understand pathological hypertrophy with HuR as a key signaling node downstream of Gq activation in the hypertrophic myocyte. Our proposed studies will determine the functional role of HuR in the development and progression of pathological hypertrophy and identify the downstream targets of HuR in hypertrophic myocytes (Aim 1). We will also determine the upstream mechanisms by which HuR is activated in the hypertrophic heart and identify HuR as a novel mediator of Gq-dependent pathological hypertrophy (Aim 2). This work is clinically significance in that we will determine whether direct inhibition of HuR has translational value as a therapeutic target for the prevention or treatment of pathological hypertrophy.